Reverse T3 interacts with αvβ3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms
| Autor: | Karin dos Santos, Fátima Regina Mena Barreto Silva, Patrícia Acordi Cesconetto, Paula Pierozan, Juliana Tonietto Domingues, Bianka Alzira Nascimento de Almeida, Regina Pessoa-Pureur, Ariane Zamoner, Daiane Cattani, Guilherme Razzera |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
endocrine system medicine.medical_specialty Aspartate transaminase Biology Biochemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Endocrinology In vivo Internal medicine Ca2+/calmodulin-dependent protein kinase medicine Receptor Molecular Biology Glial fibrillary acidic protein Glutathione 030104 developmental biology Mechanism of action chemistry biology.protein medicine.symptom hormones hormone substitutes and hormone antagonists 030217 neurology & neurosurgery Ex vivo |
| Zdroj: | Molecular and Cellular Endocrinology. 470:281-294 |
| ISSN: | 0303-7207 |
| Popis: | In the present study we provide evidence that 3,3′,5′-triiodothyronine (reverse T3, rT3) restores neurochemical parameters induced by congenital hypothyroidism in rat hippocampus. Congenital hypothyroidism was induced by adding 0.05% propylthiouracil in the drinking water from gestation day 8 and continually up to lactation day 15. In the in vivo rT3 exposure, hypothyroid 12-day old pups were daily injected with rT3 (50 ng/kg body weight) or saline until day 14. In the ex vivo rT3 treatment, hippocampal slices from 15-day-old hypothyroid pups were incubated for 30 min with or without rT3 (1 nM). We found that ex vivo and/or in vivo exposure to rT3 failed in restoring the decreased 14C-glutamate uptake; however, restored the phosphorylation of glial fibrillary acidic protein (GFAP), 45Ca2+ influx, aspartate transaminase (AST), glutamine synthetase (GS) and gamma-glutamate transferase (GGT) activities, as well as glutathione (GSH) levels in hypothyroid hippocampus. In addition, rT3 improved 14C-2-deoxy-D-glucose uptake and lactate dehydrogenase (LDH) activity. Receptor agonists/antagonists (RGD peptide and AP-5), kinase inhibitors of p38MAPK, ERK1/2, CaMKII, PKA (SB239063, PD98059, KN-93 and H89, respectively), L-type voltage-dependent calcium channel blocker (nifedipine) and intracellular calcium chelator (BAPTA-AM) were used to determine the mechanisms of the nongenomic rT3 action on GGT activity. Using molecular docking analysis, we found rT3 interaction with αvβ3 integrin receptors, nongenomically activating signaling pathways (PKA, CaMKII, p38MAPK) that restored GGT activity. We provide evidence that rT3 is an active TH metabolite and our results represent an important contribution to elucidate the nonclassical mechanism of action of this metabolite in hypothyroidism. |
| Databáze: | OpenAIRE |
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